Squamous cell carcinoma of the head and neck (SCCHN) is a devastating illness, the treatment of which is associated with significant attendant morbidity. For individuals with recurrent and/or unresectable disease, therapeutic options are limited. One potential treatment alternative for this patient population is the use of peptide-based immunotherapy. Despite the success of preclinical studies using peptide vaccines, therapeutic responses in patients have been sporadic. The reasons for failure are multifactorial and include problems with patient selection, a limited number of antigenic targets, and an inability to correlate immunologic response with therapeutic efficacy. Specifically, patients with disseminated SCCHN have defects in antigen processing, presentation, and effector mechanisms that limit their ability to respond to T cell-based immunotherapy. Additionally, a paucity of antigenic peptide epitopes are defined for SCCHN, and immunologic monitoring does not correlate well with clinical response. Recently, several investigators, including us, have identified a high prevalence of MAGE-A3 and HPV 16 on SCCHN, and characterized several putative cytolytic and helper epitopes. Additionally, we have defined a novel method to enhance the immune response to therapeutic peptide vaccines using Trojan complexes, composed of CD4 and CD8 T cell epitopes, connected by furin cleavable linkers. In order to define the feasibility and safety of these agents for the immunotherapy of SCCHN, in this proposed trial, we will screen patients for immunologic competence based on eligibility criteria including both antigen and HLA-A2 expression on tumors. In registered patients, we will test the ability of two novel Trojan peptide complexes, composed of MAGE-A3 and human papilloma virus 16 (HPV 16) epitopes, to stimulate antigen specific CD4 and CD8 T cell responses. Finally, we will correlate immunologic response with cell dose and the generation of both HPV16/MAGE-A3 antigen loss and HLA-A2 loss variants on tumors. Successful completion of this proposal will result in the development of a strong foundation for a Phase II/lll clinical trial using HPV16/MAGE-A3 Trojan peptides for the immunotherapy of SCCHN.